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Aim: There is a lack of methods for investigating the autonomic nerves of the gastrointestinal tract. Our aim was to explore a novel test measuring visceral sensory evoked potentials (EPs) in response to rapid balloon distention in the rectum and compare it to established tests for diabetic neuropathy.Method: Participants with longstanding type 2 diabetes, newly onset, untreated diabetes Results: The pressure at earliest sensation was higher in people with diabetes, 0.038 (0.012) bar vs. controls 0.030 (0.009) bar, p = 0.002, and in people with signs of peripheral neuropathy, 0.045 (0.014) bar, p < 0.01. Clinical correlations between EP amplitude and latency, and other tests were found.Conclusions: Rectal hyposensitivity was associated with both longstanding and early diabetes, indicating enteric sensory dysfunction already in early stages of diabetes. Correlation analyses may indicate that central afferent processing is affected in parallel with peripheral neuronal function. Aim: There is a lack of methods for investigating the autonomic nerves of the gastrointestinal tract. Our aim was to explore a novel test measuring visceral sensory evoked potentials (EPs) in response to rapid balloon distention in the rectum and compare it to established tests for diabetic neuropathy. Method: Participants with longstanding type 2 diabetes, newly onset, untreated diabetes

Diabetic polyneuropathy affects 30–50% of patients with diabetes mellitus. It encompasses several neuropathic syndromes, the commonest being distal symmetrical polyneuropathy or ‘diabetic peripheral neuropathy’ (DPN). Risk factors for DPN include poor glycaemic control and drivers of macrovascular disease including hypertension. Strong evidence in humans and animals implicates nerve ischaemia as the cause of DPN. Despite several well-designed recent trials, no novel approved treatment with unequivocal effects on the decline in nerve function in DPN has emerged. Painful DPN affects 15–26% of those with diabetes, produces considerable disability, and is challenging to assess and manage. First-line therapies are tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors (e.g. duloxetine) or anticonvulsants (e.g. pregabalin, gabapentin). Second-line drugs include opioids. Diabetic autonomic neuropathy also results in considerable morbidity, reduced quality of life and increased mortality. It may involve cardiovascular, gastrointestinal, urogenital, pupillomotor, thermoregulatory and sudomotor function. Although counselling and non-pharmacological interventions are of some use, more severely afflicted patients require pharmacological intervention.

Diabetic autonomic neuropathy (DAN) is one of the least understood and attended complications which affects the quality of life. Increased oxidative stress, advanced glycation end products (AGEs), overactivation of protein kinase C (PKC) and reduced myoinositol content in autonomic nerves are major pathological conditions responsible for DAN. Limited treatment options appeal researchers to search for alternative treatments for DAN. Natural polyphenols are potent antioxidants and have been reported to have beneficial effects in above mentioned pathological conditions. Diabetes was induced in male Sprague Dawley rats weighing between 190-220 g with streptozotocin (55 mg/kg, i.p.). After 6 weeks of diabetes induction, animals were treated with catechin at dose 25 and 50 mg/kg for the next 28 days. Catechin treatment at dose 25 and 50 mg/kg showed significant improvement in body weight. The treatment with catechin at dose 50 mg/kg; significantly reduced heart hypertrophy (p 0.001) and plasma glucose levels (p 0.01). At dose 50 mg/kg catechin significantly improved hemodynamic parameters like heart rate, mean atrial pressure and left ventricular systolic pressure. Catechin also improved oxidative stress parameters in the nerves. Circulatory MMP-9 levels were significantly decreased (p 0.001) in catechin treated animals at a dose of 50 mg/kg. The histopathology results showed a significant reduction in neuronal damage due to catechin treatment for 28 days. The results of the study showed that catechin has a beneficial effect in the management of diabetic autonomic neuropathy in rats.

Aim This study evaluated the association of Heart rate variability (HRV) measurements with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes. Methods This study included 102 Korean subjects with type 2 diabetes. The Michigan neuropathy screening instrument (MNSI) questionnaire score, the MNSI examination score (MNSIES) and the total symptom score were examined for DPN evaluation. Noninvasive HRV measurements were performed using photoelectric plethysmography. Patients with a MNSIES > 2 were considered to have DPN. Results The MNSIES showed significant negative associations with the high frequency (HF) (r = −0.212, p = 0.033) and low frequency (LF) (r = −0.286, p = 0.004) powers. Multiple linear regression analysis revealed that only HF power maintained a significant negative association with the MNSIES (β = −0.184; 95% CI −0.365 to −0.003; p = 0.047), after controlling for significant related confounders, with HRV parameters in male patients with type 2 diabetes. The HF (p = 0.010) and LF (p = 0.025) powers differed significantly between male patients without and those with DPN according to the MNSIES. Conclusions This study revealed a negative association of DPN, as assessed by the MNSIES, with HF power in male patients with type 2 diabetes. DPN defined by foot examination was predictive of cardiac autonomic neuropathy.

Highlights • Cardiovascular autonomic nerve function (i.e. E/I ratio) deteriorates over time in type 1 diabetes. • HSP27, MIF and PAI-1 concentrations do not correlate with cardiovascular autonomic nerve function. • The change in HbA1c correlates negatively with the change in E/I over time. • Higher HbA1c is associated with worse cardiovascular autonomic nerve function., Aim Diabetes mellitus type 1 (T1D) has numerous complications including autonomic neuropathy, i.e. dysfunction of the autonomous nervous system. This study focuses on Heat Shock Protein 27 (HSP27), Macrophage Migration Inhibitory Factor (MIF), Plasminogen Activator Inhibitor-1 (PAI-1) and HbA1c and their possible roles in effects of diabetes on the autonomic nervous system. Methods Patients with T1D (n = 32, 41% women) were recruited in 1985 and followed up on four occasions (1989, 1993, 1998, and 2005). Autonomic function was tested using expiration/inspiration (E/I-ratio). Blood samples, i.e. HSP27 (last three occasions), MIF, PAI-1 (last two occasions) and HbA1c (five occasions), were analyzed. Results Autonomic nerve function deteriorated over time during the 20-year-period, but levels of HSP27, MIF, and PAI-1 were not associated with cardiovascular autonomic neuropathy. MIF and PAI-1 were lower in T1D than in healthy controls in 2005. Increased HbA1c correlated with a decrease in E/I-ratio. Conclusions Neither the neuroprotective substance HSP27 nor the inflammatory substances, MIF and PAI-1 were associated with measures of cardiovascular autonomic nerve function, but a deterioration of such function was observed in relation to increasing HbA1c in T1D during a 20-year follow-up period. Improved glucose control might be associated with protection against autonomic neuropathy in T1D.

A 51-year-old man with type 2 diabetes mellitus was admitted with a 2-month history of repeated episodes of transient aphasia and right hemiparesis after food intake. His blood pressure (BP) fell when the neurological deficits developed. The fall in BP after each meal was confirmed by 24-h ambulatory blood pressure monitoring (ABPM), which established the diagnosis of postprandial hypotension (PPH). Diffusion-weighted magnetic resonance imaging of the brain showed multiple high-intensity lesions at the borderzone between the anterior and middle cerebral artery (MCA) territories in the left hemisphere. Digital subtraction angiography showed tapered occlusion at the origin of the left internal carotid artery (ICA). Despite sufficient antiplatelet therapy and medication for PPH, the transient symptoms remained. Positron emission tomography scanning using H215O showed decreased cerebral blood flow with increased oxygen extraction fraction in the left MCA territory. As the symptomatic left ICA occlusion was intractable, an extracranial-intracranial (EC-IC) bypass surgery was conducted without any perioperative complications. Although PPH remained, cerebrovascular ischemic events including repeated transient ischemic attack disappeared for 2 months after surgery. The coincidence of stroke with ABPM-proved transient hypotension suggested that the brain infarcts were caused by hemodynamic changes related to PPH co-existent with the chronic left ICA occlusion. ABPM is useful in evaluating hemodynamic infarcts associated with BP fluctuation, and should be considered for patients with chronic ICA occlusion. In addition, EC-IC bypass may be a treatment option for symptomatic chronic ICA occlusion due to PPH., Highlights • This case illustrates recurrent hemodynamic ischemic stroke caused by internal carotid artery occlusion with postprandial hypotension. • Ambulatory blood pressure monitoring is useful in evaluating hemodynamic infarcts associated with blood pressure fluctuation. • Extracranial-intracranial bypass is an option for cases with symptomatic chronic internal carotid artery occlusion due to postprandial hypotension.

Despite the relatively high frequency of gastrointestinal (GI) disorders in individuals with type 1 diabetes (T1D), termed diabetic enteropathy (DE), the pathogenic mechanisms of these disorders remain to be elucidated. While previous studies have assumed that DE is a manifestation of diabetic autonomic neuropathy, other contributing factors such as enteric hormones, inflammation, and microbiota were later recognized. More recently, the emerging role of intestinal stem cells (ISCs) in several GI diseases has led to a new understanding of DE. Given the absence of diagnostic methods and the lack of broadly efficacious therapeutic remedies in DE, targeting factors and pathways that control ISC homeostasis and are dysfunctional in DE may represent a new path for the detection and cure of DE.

Diabetic autonomic neuropathy includes the sympathetic ganglionic dysfunction. P2X7 receptor in superior cervical ganglia (SCG) participated in the pathological changes of cardiac dysfunction. Abnormal expression of long noncoding RNAs (lncRNAs) was reported to be involved in nervous system diseases. Our preliminary results obtained from rat lncRNA array profiling revealed that the expression of the uc.48+ was significantly increased in the rat SCG in response to diabetic sympathetic pathology. In this study, we found that lncRNAuc.48+ and P2X7 receptor in the SCG were increased in type 2 diabetic rats and were associated with the cardiac dysfunction. The uc.48+ small interference RNA (siRNA) improved the cardiac autonomic dysfunction and decreased the up-regulation P2X7 and the ratio of phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2) to ERK1/2 in SCG of type 2 diabetic rats. In conclusion, lncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats through regulating the expression of P2X7 and ERK signaling in SCG.

Aims As the glucose tolerance of patients with diabetes worsens, autonomic nervous system (ANS) function decreases. Only a few studies, using plasma glucose, have reported on this relationship in large general populations that include people with wide range of glycemia. This study aimed to examine correlates of ANS function with special reference to HbA1c which is more stable than plasma glucose among community residents. Methods Spectral analysis was performed to assess heart rate variability (HRV) using 1-minute electrocardiogram RR interval data recordings from 7690 residents aged 35–79 years in Nagahama City, Japan. HRV parameters were log-transformed. Multiple regression analysis was performed using potential correlates. Results lnLF decreased with age (regression coefficient, −0.025; P Conclusions Although the associations were weak, age, BMI and HbA1c were inversely correlated with parasympathetic activity, while positively correlated with sympathetic activity among general residents.

Objective Activation of polyol pathway based on increased activity of aldose reductase (AR) has been implicated in the development of diabetic complications including diabetic autonomic neuropathy (DAN). The relationship between DAN and hyperglycemia-induced activation of polyol pathway is still uncertain. In the present study, we investigate the association between aldose reductase activity and diabetic autonomic neuropathy by measuring AR level in red blood cells (RBC). Method In this study, 145 subjects with diabetes with or without DAN and 32 subjects without diabetes have been included. All subjects have been investigated for autonomic function tests and RBC aldose reductase activity. DAN was defined if results of any 2 of the tests of parasympathetic function were abnormal. RBC aldose reductase level was determined spectrophotometrically and expressed as unit/g of hemoglobin. The values were expressed as mean ± standard deviation, and ANOVA test has been applied for comparison between groups. Results RBC aldose reductase activity was found to be significantly higher in people with diabetes with autonomic neuropathy in comparison to people with diabetes without autonomic neuropathy and healthy individuals without diabetes. Aldose reductase (AR) level ranges from 0.8 units/g Hb to 14.2 units/g Hb. The mean AR level was 8.6±2.95 units in subjects of DM with autonomic neuropathy, while mean AR level was 4.1±1.78 units and 2.0±0.89 units in people with diabetes without neuropathy and normal healthy individuals, respectively (p Conclusions High aldose reductase activity is associated with the presence of autonomic neuropathy in subjects of type 2 DM.

Diabetic autonomic neuropathy is a possible link between abnormal metabolism in type 2 diabetes mellitus (T2DM) and risk for atrial fibrillation (AF) and heart failure (HF). The aim of this study was to elucidate the association between attenuated heart rate recovery (HRR) and these manifestations of myocardial dysfunction in T2DM. Nine hundred fourteen consecutive patients with T2DM (mean age 56 ± 11 years, 508 men) without diabetes mellitus complications, with negative results on stress echocardiography, were enrolled. Patients with known cardiac disease were excluded. Demographics, clinical assessment, co-morbidities, and insulin use were collected prospectively. The association of HRR with new-onset HF and AF was sought using a Cox proportional-hazards model. There were 47 events (22 HF and 25 AF) during a median follow-up period of 7.8 years. Events were associated with age, exercise capacity, HRR, and left atrial volume index but not with baseline glycosylated hemoglobin, left ventricular mass index, or standard markers of diastolic function. In sequential Cox models for the combined outcomes, the model based on clinical data (age and gender; overall chi-square = 5.5) was not significantly improved by left atrial volume index (chi-square = 8.6, p = 0.10) or maximum METs (chi-square = 8.7, p = 0.07) but was significantly improved by adding HRR (chi-square = 19.7, p = 0.004). In addition, HRR provided significant incremental prognostic value regarding the composite end point (net reclassification improvement 19.2%, p = 0.04; integrated discrimination improvement 1.58%, p = 0.004). In conclusion, the association of HRR with subsequent HF and AF, independent of and incremental to left atrial volume index and other markers of abnormal cardiac structure and function, indicates a role for autonomic neuropathy as the link between metabolic and cardiac risk in patients with T2DM.

Impaired cutaneous blood flow and sweating dysfunction might be among the earliest manifestations of diabetic autonomic neuropathy. This study assessed the pathophysiological basis underlying skin vasomotion changes and their relation with progressive sudomotor dysfunction and other autonomic and somatic measures in subclinical diabetic feet. Laser Doppler skin perfusion was assessed on 68 diabetic and 25 control subjects. The low-frequency vasomotion was transformed into three frequency intervals 0.0095-0.021, 0.021-0.052 and 0.052-0.145 Hz, respectively, for the investigation of endothelial, neurogenic and myogenic effects on microcirculatory alterations. The diabetic patients were categorized into three groups by increasing severity of sudomotor dysfunction: SSR+ (sympathetic skin response present; 27 patients), SSR- (SSR absent; 23 patients) and at-risk (SSR absent and of preulcerative cracked skin; 18 patients). All diabetic patients underwent nerve conduction and cardiovascular autonomic studies. The total spectral and endothelial activity was significantly decreased only in the at-risk group. The SSR- group had lower neurogenic vasomotion than the SSR+ group (p

Up-regulation of 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, causes impaired cell signaling, oxidative-nitrosative stress, and inflammation. This study evaluated the role for 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies. Control and streptozotocin-diabetic wild-type and 12/15-lipoxygenase-deficient mice were maintained for 14 to 16 weeks. 12/15-lipoxygenase gene deficiency did not affect weight gain or blood glucose concentrations. Diabetic wild-type mice displayed increased sciatic nerve 12/15-lipoxygenase and 12(S)-hydroxyeicosatetraenoic acid levels. 12/15-lipoxygenase deficiency prevented or alleviated diabetes-induced thermal hypoalgesia, tactile allodynia, motor and sensory nerve conduction velocity deficits, and reduction in tibial nerve myelinated fiber diameter, but not intraepidermal nerve fiber loss. The frequencies of superior mesenteric-celiac ganglion neuritic dystrophy, the hallmark of diabetic autonomic neuropathy in mouse prevertebral sympathetic ganglia, were increased 14.8-fold and 17.2-fold in diabetic wild-type and 12/15-lipoxygenase-deficient mice, respectively. In addition, both diabetic groups displayed small (

Background and study aims Disturbed motility may explain gastrointestinal symptoms of patients with diabetic neuropathy. This study investigates the anorectal dysfunctions in diabetic autonomic neuropathy (DAN) and microangiopathy. Patients and methods The study includes 47 diabetic patients (group 1: 30 non-complicated; group 2: 17 complicated by DAN and microangiopathy) and 10 healthy non-diabetic volunteers as control subjects. Following medical history, clinical examination and laboratory investigations, the included patients were subjected to sigmoidoscopy with mucosal biopsy and anorectal manometry. Results The lower gastrointestinal symptoms (e.g., constipation, diarrhoea or faecal incontinence) were reported more in group 2 (complicated diabetic patients) than in group 1 (non-complicated diabetic patients) ( p = 0.003) . Group 2 patients had significantly higher fasting blood glucose, serum uric acid, serum creatinine and triglycerides than group 1 patients ( p ⩽ 0.001, 0.03, 0.04, p = 0.004), squeeze pressure ( p = 0.007), and higher thresholds of minimal rectal sensation and sense of desire for defaecation (all p . Group 2 patients had lower resting anal pressure ( p p = 0.02), and higher thresholds of minimal rectal sensation ( p p = 0.009) and maximum tolerable volume ( p = 0.002) than group 1 patients . Group 2b (patients with DAN and microaniopathy) had significantly lower resting anal pressure than group 2a (patients with DAN) ( p = 0.001) . Conclusion Anorectal dysfunctions occur in diabetic patients particularly when complicated by autonomic neuropathy and microangiopathy.

Introduction Diabetes mellitus (DM) has become a global epidemic with an increasing prevalence due to rapid modernization and socioeconomic development. One in six people with diabetes are at a risk of developing diabetes related complications. Diabetic autonomic neuropathy (DAN) is one of the most overlooked complications despite its significant negative impact on survival and quality of life. Damage to autonomic nerve fibres that innervate the heart and blood vessels leads to cardiac autonomic neuropathy (CAN) which has a deleterious effect on cardiovascular dynamics. A useful autonomic functions screening instrument which can be used in DM patients for their autonomic symptoms is the need of the hour. Composite autonomic symptom scale 31 (COMPASS-31), derived from original COMPASS (86 questions), has been validated in patients of small fibre polyneuropathy but its use in patients of DM has not been explored. Present study was done to assess the use of this tool for an early detection of autonomic neuropathy in the patients of type 2 DM. Methods Sixty consecutive patients of type 2 DM of both gender and ages more than 18 years were enrolled from the medicine/neurology outpatient department according to the criteria laid by American Diabetic Association 2016. All patients were evaluated for fasting and postprandial blood glucose level,HbA1c, urine routine and microscopy, serum ceatinine, fundus examination, nerve conduction studies by Nihon kohden (Neuropack) electrophysiological apparatus, autonomic function testing by ewing’s battery of tests and heart rate variability measures (HRV). Basic clinicoepidemiologic data and COMPASS-31 Questionnaire were also collected from the participants. Results Of the 60 patients enrolled 6 patients could not get evaluated for the entire battery of tests and thus 54 patients with complete data were finally considered for analysis. There were 29 (53.7%) males and 25(46.3%) females. The median duration of illness was 7 yrs (minimum 2 months to maximum 24 years). None of the autonomic tests including SSR could show statistically significant association with COMPASS-31 scores. Individual domains of COMPASS-31 also did not show any association with objective autonomic tests. HRV parameters did not show any correlation with COMPASS-31 scores. Conclusion Standard autonomic function test are very time consuming and exhaustive to be performed on routine basis in outpatient department. Present study was planned to assess COMPASS-31 in diabetic patients to detect early autonomic dysfunction. To make it objective, standard autonomic function test was also done in all the patients. Although COMPASS-31 Scales has been validated in patients with small fibre polyneuropathy for assessing autonomic dysfunction, we could not get a significant association between COMPASS-31 and any of the objective tests. Probably COMPASS-31 scores alone is not a very sensitive screening tool for assessment of autonomic dysfunction among the patients of type 2 DM.

Cardiac autonomic neuropathy (CAN) is the most frequent and clinically important form of diabetic autonomic neuropathy. CAN is associated with increased frequency of other microvascular complications of diabetes mellitus (DM). In this study, we evaluated the prevalence diabetic nephropathy, retinopathy, and peripheral neuropathy, and measured gastric emptying time and bladder emptying time in type 2 diabetic patients with varying degrees of CAN.Fifty-three patients with DM complicated by CAN (30 women and 23 men; mean age, 58.8+/-9.15 years; duration of diabetes, 13.9+/-7.7 years) were included in this study. The patients were grouped according to the degree of CAN as early, definite, and severe CAN.There were significant differences regarding the prevalence of nephropathy, retinopathy, and peripheral neuropathy diagnosed by EMG among those groups (P.05). However, there was no significant difference regarding the prevalence of peripheral neuropathy diagnosed by neurological examination (P.05), and scintigraphic measurements of gastric and bladder emptying time were comparable among the groups (P.05).The prevalence of other diabetic microvascular complications increase as the severity of CAN increases in patients with type 2 DM. This study emphasizes the need for an early screening for peripheral neuropathy, retinopathy, and nephropathy in type 2 diabetic patients with CAN, especially with severe involvement.

Non-Obese Diabetic (NOD) mice show profound pathomorphological changes in sympathetic ganglia during the development of type 1 diabetes mellitus. We tested the hypothesis that NOD mice represent an experimental model to investigate cardiovascular changes seen in humans with diabetic autonomic neuropathy. Blood glucose (BG) levels were measured once a week. Diabetes mellitus was diagnosed as BG levels exceeded 250 mg/dl twice. NOD mice that did not become diabetic served as control group. Blood pressure (BP) and heart rate (HR) were monitored by telemetry and baroreflex sensitivity (BRS) was calculated with the sequence method or with cross spectral analysis. The measurements were obtained before onset of diabetes and during the 4th week of diabetes. The onset of diabetes was accompanied by a continuous decline in HR (615+/-14 vs. 498+/-23 bpm), whereas BP values remained stable (108+/-2 vs. 111+/-2 mm Hg). The circadian HR rhythm increased in diabetic NOD mice. BRS was higher in diabetic NOD mice than in controls. Atropine reduced BRS more profoundly in diabetic mice compared to non-diabetic mice. Despite pathomorphological similarities of the diabetic autonomic neuropathy between patients with diabetes and diabetic NOD mice, the changes in blood pressure regulation are different. In conclusion the use of diabetic NOD mice as a functional model for human diabetes may be questioned.

Objective: To review the clinical manifestations and current treatment options for diabetic neuropathies, one of the most common complications of diabetes mellitus. Methods: We performed a MEDLINE search of the English-language literature using a combination of words (diabetic neuropathy, diabetic autonomic neuropathy, diagnosis and treatment) to identify original studies, consensus statements, and reviews on diabetic neuropathies published in the past 25 years. Emphasis was placed on clinical manifestations of distal polyneuropathy and its treatment, especially new therapies. Results: Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, usually involves small and large nerve fibers. Small-nerve fiber neuropathy often presents with pain and loss of intraepidermal nerve fibers, but without objective signs or electrophysiologic evidence of nerve damage. This type of neuropathy is a component of impaired glucose tolerance and the metabolic syndrome. The greatest risk from small-fiber neuropathy is foot ulceration and subsequent gangrene and amputation. Large-nerve fiber neuropathy produces numbness, ataxia, and incoordination, thus impairing activities of daily living and causing falls and fractures. Successfully treating diabetic neuropathy requires addressing the underlying pathogenic mechanisms, treating symptoms to improve quality of life, and preventing progression and complications of diabetes mellitus. Two new drugs, duloxetine hydrochloride and pregabalin, have recently been approved for treatment of neuropathic pain associated with diabetes mellitus. Conclusion: Symptomatic therapy has become available and newer and better treatment modalities, based on etiologic factors, are being explored with potential for clinically significant reduction of morbidity and mortality. Preventive strategies and patient and physician education still remain key factors in reducing complication rates and mortality.

Diabetes mellitus compromises nitric oxide (NO)-mediated endothelium-dependent relaxation of blood vessels, which has been linked to the excessive generation of reactive oxygen species. There are also deleterious effect on nitrergic innervation, contributing to autonomic neuropathy symptoms such as impotence and gastroporesis. Poly(ADP-ribose) polymerase (PARP) is a nuclear protein stimulated by DNA damage, caused, for example, by oxidative stress. Activation has been linked to impaired endothelial nitric oxide synthase (eNOS)-mediated vasodilation in experimental diabetes. There is no information on the potential role of PARP in nitrergic nerve dysfunction, therefore, the aim was to examine the effects of PARP inhibition, using 3-aminobenzamide (3-AB) on neurally mediated gastric fundus relaxation in streptozotocin-induced diabetic rats. Eight weeks of diabetes caused a 42.5% deficit in maximum relaxation of in vitro gastric fundus strips to electrical stimulation of the non-adrenergic non-cholinergic innervation. This was largely prevented or corrected (4 weeks of treatment following 4 weeks of untreated diabetes) by 3-AB. Diabetes also markedly attenuated the maintenance of relaxation responses to prolonged stimulation, and this was partially corrected by 3-AB treatment. Experiments in the presence of the NOS inhibitor, NG-nitro- l -arginine, and/or blockade of the co-transmitter, vasoactive intestinal polypeptide, by α-chymotrypsin, showed that the beneficial effects of 3-AB were primarily due to improved nitrergic neurotransmission. Thus, PARP plays an important role in defective nitrergic neurotransmission in experimental diabetes, which may have therapeutic implications for treatment of aspects of diabetic autonomic neuropathy.

Although the (13)C-octanoic acid breath test (OBT) has been applied to diabetic patients for assessing gastric emptying, such studies are still limited. Gastric emptying was measured using solid meal containing (13)C-octanoic acid in 52 patients with Type 2 diabetes mellitus and 4 diabetic patients with mitochondrial DNA (mitDNA) 3243 mutation. Delayed gastric emptying was detected in 29% of patients with Type 2 diabetes mellitus, and multiple regression analysis showed that gastric emptying was independently associated with gastrointestinal symptoms and cardiac autonomic neuropathy. Gastric emptying was not related to gastric dysrhythmia in cutaneous electrogastrography (EGG). Diabetic patients with mitDNA 3243 mutation showed delayed gastric emptying. Because the pathogenesis of delayed gastric emptying is multifactorial in diabetic patients, the recently developed OBT is useful for studying gastric emptying in various clinical settings of diabetic patients.

The autonomic neuropathies are a group of disorders in which the small, lightly myelinated and unmyelinated autonomic nerve fibres are selectively targeted. Autonomic features, which involve the cardiovascular, gastrointestinal, urogenital, sudomotor, and pupillomotor systems, occur in varying combination in these disorders. Diabetes is the most common cause of autonomic neuropathy in more developed countries. Autonomic neuropathies can also occur as a result of amyloid deposition, after acute infection, as part of a paraneoplastic syndrome, and after exposure to neurotoxins including therapeutic drugs. Certain antibodies (eg, anti-Hu and those directed against neuronal nicotinic acetylcholine receptor) are associated with autonomic signs and symptoms. There are several familial autonomic neuropathies with autosomal dominant, autosomal recessive, or X-linked patterns of inheritance. Autonomic dysfunction can occur in association with specific infections. The availability of sensitive and reproducible measures of autonomic function has improved physicians' ability to diagnose these disorders.

Although diabetic autonomic neuropathy involves most organs, diagnosis is largely based on cardiovascular tests. Light reflex pupillography (LRP) non-invasively evaluates pupillary autonomic function. We tested whether LRP demonstrates autonomic pupillary dysfunction in diabetics independently from cardiac autonomic neuropathy (CAN) or peripheral neuropathy (PN). In 36 type-II diabetics (39-84 years) and 36 controls (35-78 years), we performed LRP. We determined diameter (PD), early and late re-dilation velocities (DV) as sympathetic parameters and reflex amplitude (RA) and constriction velocity (CV) as parasympathetic pupillary indices. We assessed the frequency of CAN using heart rate variability tests and evaluated the frequency of PN using neurological examination, nerve conduction studies, thermal and vibratory threshold determination. Twenty-eight (77.8%) patients had abnormal pupillography results, but only 20 patients (56%) had signs of PN or CAN. In nine patients with PN, only pupillography identified autonomic neuropathy. Four patients had pupillary dysfunction but no CAN or PN. In comparison to controls, patients had reduced PD, late DV, RA and CV indicating sympathetic and parasympathetic dysfunction. The incidence and severity of pupillary abnormalities did not differ between patients with and without CAN or PN. LRP demonstrates sympathetic and parasympathetic pupillary dysfunction independently from PN or CAN and thus refines the diagnosis of autonomic neuropathy in type-II diabetics.

To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings. STZ-induced diabetic mice develop identical changes, although at a much slower pace and to a lesser degree than NOD mice. NOD-SCID mice, which are genetically identical to NOD mice except for the absence of T and B cells, do not develop diabetes or neuropathology comparable to diabetic NOD mice. However, STZ-treated NOD-SCID mice develop severe neuritic dystrophy, evidence against an exclusively autoimmune pathogenesis for autonomic neuropathy in this model. Chronically diabetic type 2 db/db mice fail to develop neuritic dystrophy, suggesting that hyperglycemia alone may not be the critical and sufficient element. The NOD mouse appears to be a valuable model of diabetic sympathetic autonomic neuropathy with unambiguous, rapidly developing neuropathology which corresponds closely to the characteristic pathology of other rodent models and man.

Orthostatic hypotension in patients with cobalamin (Cbl) deficiency has been reported previously in isolated cases but we are not aware of detailed systematic studies of hemodynamic and autonomic nervous system function in patients with cobalamin deficiency. We investigated hemodynamic and autonomic responses to 60 degrees passive head up tilt (HUT) in 21 patients with vitamin B12 deficiency, 21 healthy age-matched control subjects and 9 age-matched patients with diabetes mellitus (DM) and established diabetic neuropathy. To systematically assess hemodynamic and autonomic nervous system function, we performed measurements of heart rate, beat-to-beat systolic and diastolic blood pressure, stroke index, cardiac index, total peripheral resistance index, total power, low (LF) and high (HF) frequency oscillatory component of heart rate variability, LF/HF ratio and spontaneous baroreflex sensitivity. As compared to controls, we found a significant fall of systolic blood pressure during 60 consecutive beats directly after head up tilt; furthermore, a significantly blunted fall of stroke index, cardiac index and a lack of increase of total peripheral resistance index for the duration of tilt in patients with diabetes mellitus and in patients with vitamin B12 deficiency. As compared to controls, we observed an altered response of spectral indices of sympathetic activation and vagal withdrawal and an impaired modulation of baroreflex sensitivity during head up tilt suggestive of a complex modification in the neural control activities in patients with cobalamin deficiency, which was comparable to that observed in patients with diabetes mellitus and established autonomic neuropathy. The results suggest that vitamin B12 deficiency causes autonomic dysfunction with similar hemodynamic consequences and patterns of autonomic failure as seen in diabetic autonomic neuropathy. Defective sympathetic activation may be the cause for orthostatic hypotension, which is occasionally seen in patients with vitamin B12 deficiency. It is concluded that patients with orthostatic hypotension should be screened for cobalamin deficiency.

Recent studies have reported that rat sympathetic neurons exposed to increased concentrations of glucose in vitro initiate an apoptotic program which culminates in neuronal cell death, a process proposed to contribute to the development of human diabetic autonomic neuropathy. We tested this hypothesis in an in vivo streptozotocin model of diabetic autonomic neuropathy using an unbiased counting method to quantitate neuron numbers in control and diabetic rats. Ten months of severe untreated diabetes failed to produce significant neuron loss in either the rat superior mesenteric or superior cervical sympathetic ganglia indicating that apoptotic neuronal cell death is unlikely to play a role in the pathogenesis of experimental diabetic autonomic neuropathy.

Diabetic autonomic neuropathy is a common complication following prolonged diabetes. Alterations of cardiovascular reflexes contribute to the increased cardiovascular morbidity and mortality seen in diabetic patients. This study sought to better characterize these complications by investigating the afferent limb of the baroreceptor reflex in an experimental rat model of diabetes. Streptozotocin (STZ)-induced diabetic and euglycemic control rats were studied at 8- and 16-week time points after initiation of the experiment. Activation of the afferent limb of the baroreceptor reflex was assessed by measuring the numbers of c-Fos-immunoreactive (ir) neurons in the CNS site of termination of the baroreceptor afferent neurons, the nucleus of the solitary tract (NTS). Initial experiments established that baseline cardiovascular parameters and NTS expression of c-Fos-ir neurons were not different between diabetic and control rats at either time point. Phenylephrine (PE)-induced activation of baroreceptors resulted in a significant elevation in the numbers of c-Fos-ir neurons in the NTS of control rats. Although diabetic rats showed similar pressor responses to PE, the activation of c-Fos-ir neurons in the NTS of diabetic rats was significantly attenuated. At both 8 and 16 weeks, STZ-induced diabetic rats had significantly fewer c-Fos-ir neurons in the commissural NTS and in the caudal subpostrernal NTS when compared to the non-diabetic control animals receiving PE. These data suggest that STZ-induced diabetes, for a period of 8 and 16 weeks, results in reduced activity in the afferent baroreceptor input to the NTS, and are consistent with diabetes-induced damage to baroreceptor afferent nerves.

Background: Several methods are used to study heart rate variability, but they have limitations, which might be overcome by the use of a three-dimensional return map. Objectives: To evaluate the performance of three-dimensional return map-derived indices to detect (1) sympathetic and parasympathetic modulation to the sinus node and (2) autonomic dysfunction in diabetic patients. Methods: Six healthy subjects underwent partial and total pharmacological autonomic blockade in a protocol that incorporated vagal and sympathetic predominance. Twenty-two patients with type 2 diabetes mellitus and 12 normal controls participated in the subsequent validation experiment. Three-dimensional return maps were constructed by plotting RR n intervals versus the difference between adjacent RR intervals [(RR n+1 )-(RR n )] versus the number of counts, and four derived indices (P 1 , P 2 , P 3 , MN) were created for quantification. Results: Both indices P 1 and MN were significantly increased after sympathetic blockade with propranolol, while all indices except P 1 were modified after parasympathetic blockade (P < 0.05). During the validation experiments, P 1 and MN detected differences between normal controls, and diabetic patients with and without autonomic neuropathy. The overall accuracy of most three-dimensional indices to detect autonomic dysfunction, estimated by the area under the ROC curve, was significantly better than traditional time domain indices. Three-dimensional return map-derived indices also showed adequate reproducibility on two different recording days (intra-class correlation coefficients of 0.69 to 0.82; P < 0.001). Conclusions: Three-dimensional return map-derived indices are reproducible, quantify parasympathetic as well as sympathetic modulation to the sinus node, and are capable of detecting autonomic dysfunction in diabetic patients.

Recent studies have suggested a role for neurotrophic substances in the pathogenesis and treatment of diabetic neuropathy. In this study, the effect of insulin-like growth factor I (IGF-I) on diabetic sympathetic autonomic neuropathy was examined in an experimental streptozotocin-induced diabetic rat model. Two months of IGF-I treatment of chronically diabetic rats with established neuroaxonal dystrophy (the neuropathological hallmark of the disease) involving the superior mesenteric ganglion and ileal mesenteric nerves resulted in nearly complete normalization of the frequency of neuroaxonal dystrophy in both sites without altering the severity of diabetes. Treatment with low-dose insulin (to control for the transient glucose-lowering effects of IGF-I) failed to affect the frequency of ganglionic or mesenteric nerve neuroaxonal dystrophy or the severity of diabetes. The striking improvement in the severity of diabetic autonomic neuropathy shown with IGF-I treatment in these studies and the fidelity of the rat model to findings in diabetic human sympathetic ganglia provide promise for the development of new clinical therapeutic strategies.

The potential of the aldose reductase inhibitor tolrestat to ameliorate definite diabetic autonomic neuropathy (DAN), as defined by standard cardiovascular autonomic function tests, was evaluated in 35 patients over a period of 2 years, with repeated measurements at 3-month intervals. The effect of tolrestat (200 mg a day) was compared with that of placebo on 35 controls with diabetes mellitus, of similar age, gender, and glycemic control. In the placebo group, a significant deterioration of the indices, with the exception of Valsalva ratio, was recorded, while tolrestat induced a significant beneficial change in the values of most standard cardiovascular reflex tests, in comparison to baseline and placebo. The deep breathing tests (expiration-inspiration ratio, standard deviation, and mean circular resultant of R-R intervals), postural index, and postural hypotension were favorably affected. Three of 35 patients on tolrestat (8.6%) developed high transaminases levels (more than threefold the upper normal limit) and were withdrawn from the study. In conclusion, tolrestat improved autonomic nervous system function in patients with definite DAN, in comparison to baseline and placebo. The clinical importance of this finding needs further investigation.

Recent studies have linked autoimmunity to nervous tissue structures and diabetic autonomic neuropathy, but data on the early stage of IDDM and on the natural history of this association are not available. For this reason, we investigated autonomic nervous function, and the presence of autoantibodies to sympathetic and parasympathetic nervous structures, to glutamic acid decarboxylase (GAD) and tyrosine phosphatase (IA-2/ICA512) in 85 adolescents with insulin-dependent diabetes mellitus (IDDM) (mean age 14.7+/-1.6 yr, mean duration of diabetes 6.8+/-3.5 yr), and 45 age and sex-matched healthy subjects. Nervous tissues autoantibodies were detected using an indirect immunofluorescent complement-fixation technique, with monkey adrenal gland, rabbit cervical ganglia and vagus nerve as substrates. GAD and IA-2/ICA512 autoantibodies were detected by radioimmunoprecipitation assay. Seven patients (8%) had anti-vagus nerve autoantibodies, 7 other patients (8%) had anti-cervical ganglia autoantibodies, while all controls were negative (P < 0.05). Anti-adrenal medulla antibodies were detected in 16 patients (19%) and in 2 control subjects (P

The sympathetic nervous system is of major importance in the regulation of numerous physiological functions. While it is clearly established that there is a decreased noradrenergic status in people with autonomic neuropathy, the epinephrine secretion is much more controversial. Basal and mental stress-stimulated plasma catecholamine levels were measured in 42 diabetic patients with and without pathological cardiovascular function tests and in 13 healthy, non-diabetic control subjects. In addition, the excretion of catecholamines was measured in a 24 h urine collection and compared with the stress stimulated plasma levels. During mental stress exposure a diminished epinephrine secretion was found in diabetic patients with autonomic neuropathy compared with diabetic patients without neuropathy and the healthy control group (p < 0.05: respectively). The decreased epinephrine response to mental stress was strongly correlated with a diminished urinary excretion of this "neurotransmitter' (r = 0.46; p < 0.01). Diabetic patients suffering from cardiovascular autonomic neuropathy exhibit a diminished sympatho-adrenal response following mental stress exposure. Both measurement of urinary and mental stress stimulated plasma epinephrine levels following mental stress provide reliable information regarding sympatho-adrenal activity in diabetic patients.

We report a case of a woman with several and severe disabling manifestations of autonomic neuropathy in whom reasonable quality of life was established by combining continuous insulin infusion, jejenal feeding, colostomy and bladder self-catheterisation. We discuss the prevalence rates, pathophysiology, management and prognosis of this disabling condition.

Different methods of heart rate variation (HRV) measurement are recommended to assess disturbances of cardiovascular reflexes in autonomic polyneuropathies. Influencing factors on the E/I-ratio, HRV variations during Valsalva's maneuver, and change of position from lying down to standing up, as well as age, gender, time of day and satiety were investigated in healthy volunteers. Normal values were then calculated and a total of 100 diabetics with clinically manifest neuropathy of different stages (N0 = 8, N1 = 15, N2a = 24, N2b = 28, N3 = 25), 26 of whom were insulin-dependent and 74 non-insulin-dependent, were examined. Apart from clinical examination, nerve conduction velocity (NCV) measurement of five nerves as well as amplitude measurement of evoked sensory and motor action potentials was performed. No significant influence of the time of day the test was performed could be found. Test reproducibility was good, day-to-day differences did not reach a significant level. This was also true for the test results before and after food intake. Gender-correlated test result differences could not be proven. Statistical analysis showed significant differences between the overall group of diabetics and controls. The difference was most accentuated in the E/I ratio. The further developed the clinical picture of neuropathy, the more pathological were the results obtained in different tests. The results suggest that most changes leading to pathological values of NCV and HRV occur in a clinical stage in which no, or only very slight, clinical signs give evidence of diabetic neuropathy (N0-N1). Therefore, these examinations should, especially, be performed in diabetics with no, or only slight, clinical signs of neuropathy in order to reveal those patients with neuropathic disturbances at an initial stage.

We encountered two patients with non-insulin-dependent diabetes mellitus (DM) who developed normocytic normochromic anemia. Routine hematological examinations revealed no specific causes except for the reduced serum levels of erythropoietin. Since their renal functions were preserved, the anemias may not have been due to chronic renal failure. Treatment with human recombinant erythropoietin (rHuEPO) improved anemia, ascribing the cause of anemia to low levels of erythropoietin in these patients. Underlying common clinical features of the two patients were longstanding poorly controlled diabetes mellitus accompanied with advanced neuropathy. Since erythropoietin production is regulated in part by autonomic nervous system, the results suggest that erythropoietin production could be prematurely impaired in patients with severe diabetic autonomic neuropathy.

Emerging evidence suggests that distal symmetric sensorimotor polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN) stems from nerve dysfunction in early stage of diabetes. Neurophysiological assessment can provide an early diagnosis of such complications and should be carried out at the diagnosis and during progression of the disease. We studied 44 patients, 24 type 2 diabetes (mean age 61 years, duration 14 years, mean HBA 1 C 8,2%) and 20 type 1 (mean age 19 years, duration 11 years, mean HBA 1 C 8,4%). All subjects complained of symptoms proper to peripheral neuropathy. Neurophysiological evaluation included Nerve Conduction Studies/Electromiography, Heart Rate Variability including time domains (mean RR-interval and RR-standard deviation), Sympathetic Skin Response (SSR). Peripheral neuropathies due to any other cause were excluded. The prevalence of DSPN, DAN and the association between DSPN and DAN was significantly higher in patients with type 2 compared with those with type 1 diabetes ( P P = 0,01) in type 2 diabetes patients. Poor glycemic control and the disease duration are some of the concurrent factors in diabetic polyneuropathy and CAN pathogenesis. Since DSPN and DAN probably share the same pathogenesis, neurophysiological follow-up should be considered as a useful tool for early diagnosis of such complications. In our opinion, however, mean duration of diabetes and the age could be an important etiologic factor of PNS.

To elucidate the relationship between diabetic autonomic neuropathy and gastrointestinal motility, antroduodenal motility was studied in patients with diabetes using duplex sonography.Antroduodenal motility, transpyloric fluid movement, and velocity curves of fluid flow were studied using duplex sonography in 32 patients with diabetes and 10 healthy subjects after their ingestion of a meat soup.The frequency of antroduodenal coordination was significantly reduced in patients with diabetes with both early and definite autonomic neuropathy compared with healthy subjects (P0.05 and P0.01, respectively). The frequency and duration of end-cycle reflux episodes were also significantly reduced in patients with early and definite autonomic neuropathy compared with healthy subjects (P0.05 and P0.01, respectively). The frequency of end-cycle reflux episodes was closely correlated with the frequency of antroduodenal coordination in both healthy subjects (r = 0.859; P = 0.002) and patients with diabetes (r = 0.929; P = 0.0001). There was a significant correlation between fasting plasma glucose concentrations and the frequency of antroduodenal coordination in patients with diabetes (r = -0.361; P = 0.039).These findings suggest that reduced frequency and duration of end-cycle reflux episodes may be an early indicator of diabetic gastroparesis that may be related mainly to autonomic neuropathy but also in part to acute hyperglycemia.

To investigate the relationship between diabetic autonomic and peripheral neuropathies, we carried out power spectral analysis (PSA) of heart rate variations and determined the vibratory perception threshold (VPT) in diabetic subjects (DM). The VPT, measured with a Suzuki-Matsuoka Vibrometer (SMV-5), was greater in diabetic subjects than in controls. The low frequency (LF) component of the PSA which represents sympathetic nervous activity and the high frequency (HF) component of the PSA which indicates parasympathetic nervous activity were significantly decreased in diabetic subjects when compared to values in the controls. In addition, there were significant inverse correlations between the LF and HF components of the PSA of heart rate variations and the VPT. These results suggest that the PSA of heart rate variations and the measurement of VPT are useful tools for evaluating diabetic autonomic and peripheral neuropathies.

Patients with diabetic autonomic neuropathy (DAN) exhibit decreased heart rate variability (HRV) and are prone to sudden death. When HRV was used as an index of DAN, the circadian rhythmicity of heart rate and QT intervals was studied in 17 patients with diabetes who had varying degrees of DAN and 13 healthy control subjects. Heart rate and QT and QTc intervals for all subjects were found to exhibit a significant circadian periodicity. Heart rate was lowest and QT and QTc intervals were longest between midnight and 6:00 AM; heart rate increased and QT and QTc intervals shortened in the hours after waking. The diabetic group with more severe autonomic neuropathy (DAN+, HRV = 76 +/- 20 msec, n = 7) had significantly higher heart rate and shorter QT and QTc intervals compared with the diabetic group without autonomic neuropathy (DAN-, HRV = 120 +/- 13 msec, n = 10) or healthy control subjects (CT, HRV = 119 +/- 26 msec, n = 13). Twenty-four-hour mean heart rate was 90 +/- 7 beats/min (range, 79 to 98 beats/min) for DAN+, 77 +/- 8 beats/min (range, 64 to 86 beats/min) for DAN- (DAN+ vs DAN-; p = 0.005), and 74 +/- 7 beats/min (range, 64 to 80 beats/min) for CT (DAN+ vs CT; p = 0.0004). Mean 24-hour QTc was 391 +/- 13 msec (range, 387 to 399) msec for DAN+, 417 +/- 19 msec (range, 413 to 425 msec) for DAN- (DAN+ vs DAN-; p = 0.01), and 412 +/- 28 msec (range, 408 to 419 msec) for CT (DAN+ vs CT; p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

This study attempted to determine whether postprandial hypotension (PPH) is associated with diabetes mellitus by 24-h ambulatory blood pressure monitoring (24-h ABPM) and by monitoring blood pressure during 75-g oral glucose tolerance test (75-g OGTT) in 15 normal subjects and 35 patients with non-insulin-dependent diabetes mellitus. When we defined PPH as a postprandial decrease in systolic blood pressure of greater than 20 mmHg, the incidence of PPH in diabetics was 37% by 24-h ABPM and 20% by 75-g OGTT. The incidence of proliferative retinopathy and proteinuria was greater in diabetics with PPH than in those without PPH. All of the patients with PPH had somatic and autonomic neuropathy. The C-peptide response was lower in diabetics with PPH than in those without PPH. We revealed the presence of PPH in diabetics, and found that PPH was closely related to disease severity, especially diabetic autonomic neuropathy.

In a group of 46 consecutive outpatients attending the diabetic clinic of our Metabolic Department, 30 insulin-dependent and 16 non-insulin-dependent diabetic patients in stable metabolic control, and in 38 age-matched controls, we measured vibration perception threshold with biothesiometer and autonomic function, by means of the five classical cardiovascular tests: R-R interval variations during deep breathing, Valsalva ratio, lying-to-standing, postural hypotension, and sustained handgrip. None of the patients complained of symptoms related to diabetic autonomic neuropathy (DAN) or sensory polyneuropathy. Vibration perception threshold positively correlated with Valsalva ratio (p0.05) and deep breathing (p0.01), and all of them correlated with age (p0.001), but not with duration of diabetes and metabolic control. Patients scored significantly lower than controls in vibration perception threshold and all of the autonomic function tests. According to the outcomes of cardiovascular tests ["Autonomic Score" (AS)] patients were divided into two different groups: presence (DAN+ = ASor = 3) or absence (DAN- = AS3) of autonomic neuropathy. The DAN- group (n = 28, 60.9%) showed no significant differences from the DAN+ group (n = 18, 39.1%) in age, duration of diabetes, glycated hemoglobin, or body mass index. DAN+ patients had vibration perception threshold measured at the first toe tip and at external malleolus significantly higher than DAN- patients (p0.01 and p0.001, respectively) and controls (p0.005), as well as all the other cardiovascular tests except sustained handgrip. No difference in any of these items was observed between DAN- patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Twelve patients with erectile impotence related to diabetic neuropathy were treated with a vacuum device, Pos-T-Vac. Efficacy of the device and psychological evaluation (Dyadic Adjustment Scale for marital satisfaction and Hamilton Rating Scale for depression) were performed before and 3 months after treatment. Vacuum therapy was successful in 75% of the patients. Patients with successful impotence treatment and normal baseline marital satisfaction scores showed a modest increase in the scores of marital satisfaction (from 114 +/- 3 points, baseline, to 121 +/- 3 points, posttreatment; p less than 0.05). Vacuum therapy for the treatment of erectile dysfunction due to diabetic autonomic neuropathy appears to be safe and effective.

In order to determine the effect of diabetic autonomic neuropathy (DAN) on the atrial natriuretic peptide (ANP) response to dynamic stimuli, we studied the ANP response to 60 degrees head-up and 60 degrees leg-up tilt in diabetic subjects with (DAN + ve, n = 8) and without (DAN - ve, n = 8) evidence of autonomic neuropathy and seven matched non-diabetic controls. Mean baseline plasma ANP concentrations were similar in all three groups. Head-up tilt was associated with a fall in plasma ANP in all seven healthy controls (21.8 (16.8-30.7) to 16.8 (7.1-29.1), P = 0.06, mean (range)), seven of the eight DAN - ve (16.9 (6.5-33.7) to 8.5 (3.0-21.1), P = 0.015) and all eight DAN + ve subjects (27.3 (8.5-101.5) to 15.4 (1.0-67.6), P = 0.044). Leg-up tilt caused a rise in plasma ANP in six of the seven healthy controls (17.6 (7.5-27.9) to 22.4 (15.2-48.1), P = 0.041), six of the eight DAN - ve (12.5 (7.8-27.8) to 15.5 (7.3-31.3), P = 0.054) and seven of the eight DAN + ve subjects (18.2 (2.8-55.1) to 25.1 (4.5-92.8), P = 0.013). There was no significant difference in the fall in plasma ANP during head-up tilt or in the rise in plasma ANP during leg-up tilt between the three groups. We conclude that the regulation of ANP secretion is normal in diabetes mellitus, and is unaffected by the presence of autonomic neuropathy.

We examined flow velocities in the superior mesenteric artery and celiac artery in normal controls (group C, n = 11), diabetic patients (group D, n = 8), and diabetic patients with clinically evident autonomic neuropathy (group DN, n = 6) to further define the usefulness of duplex examination in the evaluation of the mesenteric circulation in normal and disease states. By use of a 3 MHz duplex scanner, peak systolic velocity, peak diastolic forward velocity, end-diastolic forward velocity, and peak diastolic reverse velocity were measured in centimeters per second before and after a standardized meal. The vessels' diameters in centimeters were also measured. After the meal peak diastolic reverse velocity disappeared in all patients. The average vessel diameter in the superior mesenteric artery (0.7 cm) and celiac artery (0.8 cm) did not change. Flow velocities in the celiac artery were not significantly altered by the meal. In the control group, peak systolic velocity in the superior mesenteric artery increased 38%, peak diastolic forward velocity rose 66%, and end-diastolic forward velocity increased by 70%. In the diabetic nonneuropathic group the changes were 15%, 98%, and 100%, respectively. These changes were statistically significant (p less than 0.01). On the other hand, the patients with diabetic autonomic neuropathy presenting a picture of gastroparesis did not exhibit the expected increases in postprandial velocities. Moreover, this alteration in blood flow velocity, although similar to that encountered in patients with intestinal angina, did not appear to be due to occlusive arterial disease on the basis of clinical examination and B-mode scanning.

Autonomic neuropathy and urinary bladder function were compared in Sprague-Dawley rats with alloxan-diabetes of 3 months duration, rats fed sucrose for 8 weeks, and rats examined 8 weeks after pelvic nerve surgical axotomy; normal age-matched rats were used as controls. All experimental interventions induced bladder hypertrophy with increased bladder weight. In diabetic and sucrose-fed animals, water intake and urinary output increased. Cystometric recordings of normal rats in vivo showed rhythmic contractions (1.25 ± 0.25 contr/min) with threshold volume for micturition reflex at 0.51 ± 0.04 ml. In diabetic rats, bladder contractions were irregular and of lower frequency (0.60 ± 0.04 contr/min), while threshold volume was significantly higher (1.00 ± 0.11 ml). Bladder contractions were normal in sucrose-fed animals, though threshold volume was markedly augmented (1.27 ± 0.19 ml). Pelvic nerve surgical ablation abolished micturition reflex. In bladder strips excised post-mortem, contractile response to field stimulation was reduced in diabetic rats compared to control and sucrose-fed animals. Morphological examination of pelvic and hypogastric nerves revealed abnormalities characteristic of diabetic neuropathy only in diabetic rats. These data suggest that in alloxan-induced diabetes the decrease in the rate of bladder contraction is the result of autonomic neuropathy; while bladder hypertrophy in sucrose-fed rats appears to be an organ adaptation to hyperdiuresis.

The influence of age on diabetic autonomic neuropathy was studied. In the present study autonomic neuropathy was assessed by cardiac beat-to-beat variation during deep breathing (BBV) and pupil area prior to photic stimulus (A1). In the studies on BBV a total of 440 subjects (11–82 years in age) were divided into three groups: those with a duration of diabetes of less than 5 years and without obvious diabetic complications; those with a duration of diabetes of longer than 5 years and with diabetic complications; and non-diabetic, healthy subjects. The relationship between BBV and age was examined in each group. In the studies on A1 a total of 101 subjects (22–75 years in age) were investigated in the same way. The results were as follows: (1) The autonomic nerve function of young diabetics corresponds to that of old non-diabetics in terms of cardiac beat-to-beat variation and pupil area prior to photic stimulus; (2) in young diabetics duration of diabetes and the complications influence the autonomic nerve function; (3) autonomic nerve function is related to age. Age is more influential than duration of diabetes and diabetic complications, especially in the older subjects.

The role of vagal mechanisms in the reversal of pharmacologically-induced bronchoconstriction by deep inspiration is unclear. We examined the effect of lung inflation on methacholine-induced bronchoconstriction in six patients with severe diabetic autonomic neuropathy compared with five patients with diabetes mellitus and normal tests of autonomic function. The effect of deep inspiration on bronchomotor tone was expressed as the ratio of maximal flow rates at 70% of expiratory vital capacity (V30) calculated from complete (V30(c)) and partial (V30(p)) flow-volume curves ( V 30(c) V 30(p) ). In patients with autonomic neuropathy the mean (range) of this ratio was 1.31 (1.19–1.47) and was not significantly different from the control patients with a mean ratio of 1.69 (1.28–2.13). These results suggest that the reversal of methacholine-induced bronchoconstriction by a deep inspiration is not mediated via vagal nerves.